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Abstract

Background

The purpose of this study was to evaluate the risk of developing pneumonia in acute
stroke patients comparing the early anatomical stroke location and laryngeal cough
reflex (LCR) testing.

Methods

A prospective study of 818 consecutive acute stroke patients utilizing a reflex cough
test (RCT), which assesses the neurological status of the LCR compared to magnetic
resonance imaging or computerized tomography for stroke location and subsequent pneumonia
outcome. Stroke diagnosis and stroke location were made by a neurologist and clinical
radiologist, respectively; both were blinded to the RCT results.

Results

Brainstem (p-value < .007) and cerebral strokes (p-value < .005) correlated with the
RCT results and pneumonia outcome. Of the 818 patients, 35 (4.3%) developed pneumonia.
Of the 736 (90%) patients who had a normal RCT, 26 (3.5%) developed pneumonia, and
of the 82 (10%) patients with an abnormal RCT, 9 (11%) developed pneumonia despite
preventive interventions (p-value < .005). The RCT had no serious adverse events.

Conclusion

The RCT acted as a reflex hammer or percussor of the LCR and neurological airway protection
and indicated pneumonia risk. Despite stroke location, patients may exhibit "brainstem
shock," a global neurological condition involving a transient or permanent impairment
of respiratory drive, reticular activating system or LCR. Recovery of these functions
may indicate emergence from brainstem shock, and help predict morbidity and mortality
outcome.

Keywords:

cough; reflex; laryngeal; stroke; pneumonia; brainstem shock

Background

The laryngeal cough reflex (LCR) protects the supraglottic larynx from significant
aspiration of food or fluids during inspiration or pharyngeal spillage during swallowing
[1]. The reflex cough test (RCT), using nebulized tartaric acid solution, provides an
effective stimulus to the receptors in the supraglottic mucosa, and, like a reflex
hammer or percussor, triggers a cascade of neurological activity in both craniospinal
nerves and the central nervous system. The vagus nerve mediates the afferent component
of the LCR. Tartaric acid-induced cough stimulates rapid adapting receptors (RARs)
in the supraglottic region of the larynx and sensory impulses are conveyed to the
medulla via the middle ramus of the internal branch of the superior laryngeal nerve
(ibSLN) and vagus nerve [2-6]. The fibers of the ibSLN terminate on neurons near the nucleus tractus solitarius
(NTS) of the medulla. The central connections of the reflex and voluntary cough circuits
have been reviewed,[7,8] Although the central connections of reflex cough are unclear, research suggests a
rapid latency [5]. Central processing of the cough reflex quickly sets off a cascade of synchronized
central and peripheral responses involving the nucleus ambiguus, retroambigualis,
phrenic nucleus, and medial motor cell column which project to the vagus, phrenic,
intercostal and thoracoabdominal nerves, respectively [9].

Human studies have indicated the clinical implications of central and peripheral lesions
of the cough system. The LCR may be impaired in individuals who have a transient (e.g.,
post-general anesthesia) or permanent (e.g., post-stroke, cervical cord trauma, Parkinson's
disease, amyotrophic lateral sclerosis) neurological event, which may affect the afferent,
central or efferent components of the LCR [10-18]. The purpose of this study was to determine the effect of identifying the initial
radiological anatomical stroke location on the laryngeal cough reflex test result
and the relationship to the subsequent risk of developing pneumonia.

Methods

This was a clinical prospective study of 818 consecutive patients during a three year
period of time, who were admitted to an acute rehabilitation hospital with a primary
diagnosis of acute stroke. Stroke diagnosis was made by a neurologist and the stroke
location was determined by a neuroradiologist, both were blinded to the RCT findings.
In this study, stroke location was noted according to computer tomography (CT) or
magnetic resonance imaging (MRI) results as reported by the radiologist in the clinical
setting. Stroke locations were categorized as: cerebral, brainstem, multiple CNS infarcts,
basal ganglion, cerebellar, or location not specified by MRI or CT report.

Upon admission to the acute rehabilitation hospital, all patients were tested with
the RCT, as the first component of a standard bedside swallow examination. The RCT
(Pneumoflex Systems, Inc., Melbourne Beach, FL) comprised a 20% solution of pharmaceutical
grade L-tartaric acid dissolved in sterile 0.15 M NaCl solution and inhaled from a
Bennett Twin Nebulizer (3012-60 ml, Puritan-Bennett Company, Carlsbad, CA). During
the inhalation, the subject's nose was pinched closed. The nebulizer output was 0.2
ml/min [1,3,19-23]. The RCT was administered at bedside by a either a respiratory therapist or speech
pathologist. The subject was asked to exhale, then insert the mouthpiece, and take
a sharp, deep inhalation. Leakage around the mouthpiece and "puffing" the nebulizer
were not considered effective inhalations. The test was administered by a either a
speech pathologist or respiratory therapist at bedside and required less than five
minutes to complete. The expected result of a normal RCT was an immediate series of
forceful coughs, which are primarily expiratory "airway clearing" in character. A
normal finding indicated a normal function of the LCR, vagus nerve, and a neurologically
protected airway. If the subject had a normal RCT, additional inhalations of the RCT
were not performed. The expected result of an abnormal RCT was represented by an absence
of coughing, or a diminished (weak) coughing, or coughing not immediately after administration
of the test stimulus. An abnormal finding indicated dysfunction of the LCR, vagus
nerve or the reflex cough system, and a neurologically unprotected airway. The RCT
was terminated when the subject either elicited a cough or failed to cough after three
valid inhalations. The subjects were then treated clinically based on the RCT findings.
The previously published RCT algorithm was followed for subsequent feeding strategies
such as restricted diet, nothing by mouth (NPO) or nutritional support via percutaneous
endoscopic gastrostomy (PEG) [1]. These treatment strategies were noted for all patients.

Subjects were monitored for the development of pneumonia during their hospital stay
of approximately one month. Pneumonia was diagnosed as a subject having respiratory
symptoms with either temperature greater than 101°, leukocytosis, or both, and an
infiltrate confirmed by chest x-ray. Adverse events of the RCT were collected for
all subjects.

Data Analysis

Statistics were generated using SPSS 10.0.5. Subjects who had either a normal or abnormal
RCT finding were statistically compared as to gender, age, and length of stay in the
acute care setting. The principal endpoint for the study was the development of pneumonia
among acute stroke patients. This endpoint is binary. An appropriate test of significance
for this situation was the Fisher's exact test with the Null Hypothesis stating that
among the acute stroke patients there is no significant difference in the development
of pneumonia, regardless of the stroke location, between patients that had a normal
RCT and those patients that had an abnormal RCT. In addition to a test of significance,
it was important to determine a 95 percent confidence interval for p1 - p2, where p1 was the proportion of acute stroke patients that developed pneumonia and had an abnormal
RCT, and p2 was the proportion of acute stroke patients that developed pneumonia and had a normal
RCT. For completeness, the odds in favor of not developing pneumonia among the patients
who had an abnormal RCT were compared to the odds in favor of not developing pneumonia
among the patients who had a normal RCT. As part of a power analysis, there are standard
formulae for determining sample sizes for the comparison of the proportions. The level
of significance, power of the test and the proportions were evaluated. The RCT results,
stroke location and pneumonia outcome were crosstabulated utilizing the Chi-Square
test.

The issue of sensitivity and specificity of the RCT in determining pneumonia risk,
though obviously important, is not appropriate to assess in this study because the
interventions, guided by the results of the RCT, can effect pneumonia outcome [1,22,24].

Results

The mean age of these patients was 73.69 ± 10.44, and included 426 males and 392 females.
The patients in this acute stroke population included more than 59 overall comorbidies.
The mean length of stay in the acute care and rehabilitation hospitals was 7.7 ± 7.7
and 31.2 ± 18.4 days, respectively. Analysis of gender, age, and length of stay in
the acute care setting indicated that there were no epidemiological differences between
subjects who had either a normal or abnormal RCT finding.

The principal endpoint for the study is the development of pneumonia. Among the 818
acute stroke patients, 736 (90%) patients had a normal RCT, of which 26 patients (3.5%)
developed pneumonia (Table 1). Eighty-two (10%) patients had an abnormal RCT, defined as weak or absent. Of the
abnormal RCT group, 69 (84%) patients had a weak RCT, of which 7 (10%) developed pneumonia.
Thirteen (16%) patients had absent RCT and 2 (15%) developed pneumonia. A significant
difference for pneumonia outcome was found (p-value < .005) (Table 2). The 95 percent confidence interval for p1 - p2 was (.04, .11), respectively. This two-sided 95 percent confidence interval clearly
showed that p1 is greater than p2. The proportion of acute stroke patients that developed pneumonia and had an abnormal
RCT was significantly greater than the proportion of acute stroke patients that developed
pneumonia and had a normal RCT. In fact, 3.5% of the patients with a normal RCT versus
11% of the patients with an abnormal (weak or absent) RCT developed pneumonia.

The odds in favor of not developing pneumonia among the patients who had an abnormal
RCT were compared to the odds in favor of not developing pneumonia among the patients
who had a normal RCT. The odds ratio test indicated that the odds in favor of not
developing pneumonia for acute stroke patients with an abnormal RCT were significantly
smaller than the odds in favor of not developing pneumonia for acute stroke patients
that had a normal RCT. In fact, the ratio of the odds was .297, which was significantly
smaller than 1, and a 95 percent confidence interval for the odds ratio was (.134,
.658). When the level of significance is fixed at 0.05, the power of a two-sided test
is 80 percent.

Stroke location, RCT results and pneumonia outcomes are shown in Table 3. Crosstabulation of the RCT results, pneumonia in rehabilitation and brainstem infarcts
was significant at identifying the risk of developing pneumonia (p = .007) as was
the crosstabulation for cerebral hemispheric infarcts (p = .005). Basal ganglionic,
cerebellar, multiple infarcts or stroke location not specified by CT or MRI did not
correlate with RCT results and predicting the development of pneumonia. Data analysis
for basal ganglion and cerebellar infarcts were not crosstabulated because none of
these patients developed pneumonia in rehabilitation.

Thirty-two (3.91%) of the 818 patients had a percutaneous endoscopic gastrostomy (PEG)
while in rehabilitation (Table 4). Ten PEGs were placed while in rehab, and 15 PEGs were removed in rehabilitation.
Seven (0.9%) of the 818 patients received a modified barium swallow (MBS) examination.

Seventeen patients (2.1%) were transferred to acute care from rehabilitation, 15 had
a normal RCT and 3 of these patients developed pneumonia in rehabilitation. Two of
the transferred patients had an abnormal RCT and neither developed pneumonia in rehabilitation.
Two of the 818 patients died in rehabilitation. One patient had a left cerebral hemispheric
infarct, and died of complications secondary to cancer. The other patient had a middle
cerebral artery infarct, and died four days after admission to the rehabilitation
hospital due to ongoing complications secondary to pneumonia acquired in acute care.

In this study, there were no serious adverse medical sequelae from RCT administration.
In the 82 stroke patients who had an abnormal RCT, there was no statistical correlation
for comorbidities such as congestive heart failure, diabetes mellitus, chronic obstructive
pulmonary disease, or patients who had been intubated.

Discussion

Nebulized tartaric acid appears to be an effective, specific and safe stimulus to
laryngeal receptors and testing neurological airway protection. This concentration
of nebulized tartaric acid-induced cough has been used in a number of cough sensitivity
studies involving normal subjects, smokers and asthmatics without causing bronchoconstriction
[19-21,25,26]. Our studies on stroke subjects and other patients with neurological impairment use
a single breath inhalation protocol similar to Choudry and Fuller [27]. When the internal branch of the superior laryngeal nerve was completely, bilaterally
anesthetized, the LCR was transiently absent in normal subjects and they could tidal
breathe nebulized tartaric acid without eliciting laryngeal or tracheobronchial cough
[4]. Testing the neurological function of the LCR may help indicate those patients who
are at risk of respiratory complications such as pneumonia.

This study reported a significant relationship among RCT results, pneumonia risk and
both brainstem and cerebral strokes. Although all subjects had a primary diagnostic
code of stroke and the initial stroke location was determined and described by a radiologist
in the clinical setting, it is not always possible to determine the extent of the
neurological deficits by the location of the infarct emergently using MRI or CT. This
study, using the present examination techniques for identifying neurological deficits
in the emergency setting showed that subjects, who had a subsequent brainstem or cerebral
hemispheric infarct identified by CT or MRI and a subsequently impaired LCR, were
at risk of developing pneumonia. Indeed, a clinician in the emergency room presently
could not test the status of a patient's involuntary neurological airway protection,
i.e., LCR, before making a decision to place a nasogastric (NG) tube or administer
food, fluid or medications orally. The use of a NG tube in the acute stroke setting,
without the knowledge of the neurological status of the LCR may be a significant contributing
factor for the development of respiratory complications such as pneumonia, ventilator
necessitation or death [28].

In the present study brainstem infarcts and cerebral hemispheric infarcts correlated
with a significant risk of developing pneumonia, although basal ganglionic, cerebellar,
multiple infarcts or stroke location not specified by CT or MRI did not correlate
with RCT results and predicting pneumonia risk. None of the patients who had a basal
ganglion and cerebellar infarct developed pneumonia in the acute rehabilitation setting.
Nakagawa and coworkers reported that the incidence of pneumonia was significantly
higher and the latency of swallowing response to the onset of was also longer in patients,
who had either unilateral or bilateral basal ganglia infarcts than in patients with
no infarct on CT [29]. However, they were studying the swallow reflex and silent aspiration during sleep
in long term care patients and did not evaluate the LCR. Since the LCR and swallowing
are separate neurological events, both must be evaluated separately. Although swallowing
function is often assessed in hospital settings, testing the LCR is not presently
performed although information as to the integrity of this vital, airway protective
reflex would be helpful in patient management [1,22].

The numerous comorbidities of this acute stroke population along with the RCT results,
stroke location, and pneumonia outcome data suggest the need to test all patients
who might have an acute neurological impairment. The overall incidence of an abnormal
RCT, in the rehabilitation setting day 4 or 5 post onset, was about 10% regardless
of stroke location. The incidence of abnormal tests on acute stroke presentation in
the emergency room would be higher. Patients with basal ganglionic, cerebellar, or
infarct location unspecified and an abnormal RCT are not necessarily false positives,
since the RCT results identified pneumonia risk and the need for appropriate intervention.

Although the central connections of the LCR are not clear in humans, the LCR probably
has reciprocal connections with supratentorial areas that modulate or modify the LCR.
Assuming adequate cognition and laryngeal sensorium, we are aware when the LCR is
triggered by a noxious laryngeal stimulus–suggesting projections to the cerebrum.
In humans a neurological interrelationship between the brainstem mediated LCR and
supratentorial influences has been reported and an amygdalo-hypothalamo-reticular
pathway has been suggested [30].

Cerebral hemispheric infarcts may, through mechanisms that are unclear at this time,
suppress the LCR circuitry. Perhaps, moderate to large cerebral hemispheric lesions
may result in neurotransmitter or neurophysiologic circuitry disruption or a downward
pressure and/or mass effect secondary to cerebral edema, which could have an adverse
effect upon these vital brainstem functions by interruption of descending facilitatory
supratentorial pathways, as in spinal shock and general anesthesia. This condition
is different from isolated brainstem lesions such alternating hemiplegias, lateral
medullary syndrome, pontocerebellar angle syndrome or other bulbar lesions.

Suppression of the LCR tends to support our clinical observations that many cerebral
hemispheric stroke patients, who show a transient or permanent impairment of the LCR,
may have a condition we refer to as "brainstem shock." Brainstem shock may be defined
as a global neurological condition involving a transient or permanent impairment of
one or more of the following vital functions: the reticular activating system, respiratory
drive, or the LCR. Frequently patients with large or small hemispheric strokes, bleeds
or infarcts, may present unconscious with a depressed reticular activating system,
or require intubation secondary to a depressed respiratory drive. Although presently
not clinically tested in the emergency room or intensive care units, airway protection
may also be impaired at this stage, and the initial emergency radiological examination
may not give adequate information regarding the patient's neurological status. Patients
in brainstem shock may recover reticular activating system function, respiratory drive,
or neurological airway protection at different rates, similar to recovery from general
anesthesia, and may be an important predictor of morbidity and mortality.

More detailed brain mapping of the lesion is not generally feasible, or available
in the clinical setting. Such technologies might elucidate the connections between
cerebral and brainstem structures associated with reflex cough, and would pose an
interesting study. Although cough may be measured using more sophisticated techniques
in the laboratory, such as electrophysiological or plethysmography, we feel that the
method for grading cough, used in this study, is appropriate for the clinical setting
as part of a comprehensive neurological examination.

Conclusion

Although instrumented exams of the CNS using MRI or CT may be an important component
of a neurological evaluation, they cannot adequately assess vital neurological functions
such as respiratory centers in the reticular formation, consciousness or airway protective
reflexes such as the LCR. Neurologists are familiar with the neurologically impaired
patient, who has an unremarkable brain imaging study or one in which the stroke location
is not specified. Although these results rarely mitigate the primary diagnosis of
stroke, clinicians must still assess the status of these vital functions. Objective
assessment of respiratory function and clinical evaluation of consciousness are commonly
performed. However, bedside testing of the LCR is not currently available, yet its
status plays an important role when the clinician must initiate a strategy for food,
fluids and medications that is safe for the patient. The RCT may be helpful for identifying
a change in neurological status or progressing cerebral edema in emergent stroke patients
before identification is possible with imaging exams, thus assist in directing urgent
care. The RCT examination may be helpful in assessing recovery of airway protection
following extubation or general anesthesia and would be important further research
for patient care.

The most powerful finding in this study is a normal RCT. In acute neurological patients,
without confounding structural head and neck conditions that may prevent physical
closure of the larynx during swallowing, a normal RCT reliably provides the opportunity
to safely and aggressively approach emergency procedures such as NG tube placement,
and the administration of food, fluids and medications in the acute setting. Further
research needs to be done on other neuropathophysiological conditions for those patients
who have an abnormal RCT. Further research on the neurological condition of brainstem
shock in acute neurological conditions needs to be performed.

Competing interests

Although none of the authors has been financially compensated for the research associated
with this research, a commercial party with a financial interest in the reflex cough
test may confer a financial benefit upon one or more of the authors. The reflex cough
test (Pneumoflex®) of the laryngeal cough reflex is patented and trademarked by Pneumoflex Systems,
LLC, Melbourne Beach, Florida. Pneumoflex® has not been used commercially in the past or present. Pneumoflex Systems, LLC, is
pursuing FDA and EU approval. Use of this technique in the health care system requires
regulatory approval.

Authors' contributions

RES and WRA conceived the study and drafted and revised the manuscript, WRA collected
all subject data, JW helped draft and revise the manuscript, and KR performed the
statistical analysis and wrote the appropriate section. All of the authors contributed
to drafting the original and revised manuscripts, and have granted final approval
of this published version.